Abstract Sleep profoundly affects emotional and motivational states. Sleep disturbance is a co-morbidity in almost all emotional and motivational disorders including drug addiction, depression, and schizophrenia. Indeed, sleep disturbance is not only a symptomatic consequence, but also a causal factor for the progression of these pathological emotional states. Clinical statistics show that people with insomnia are more prone to drug addiction. Despite such apparent significance, little is known about how sleep disturbance regulates the function of key brain regions that control emotion and motivation. This application focuses on this important yet under-explored research area. The proposed research attempts to characterize how sleep deprivation (SD) regulates both excitatory and inhibitory synapses as well as the membrane properties of neurons within the nucleus accumbens (NAc), a brain region that gates emotional and motivational output. Malfunction of the NAc contributes to several pathological emotional and motivational states, such as drug addiction, anxiety, and depression. Although clinical statistics shows a clear correlation between the intensity of sleep disturbance and the degree of these emotional disorders, it remains to be determined how NAc neurons are altered in sleep- disturbed subjects. By characterizing the effect of SD on synaptic transmission and membrane properties of NAc neurons, the proposed work will provide a relatively comprehensive picture about how sleep disturbance affects the functional output of the NAc. The central hypothesis guiding the proposed research is that SD differentially regulates excitatory and inhibitory synaptic activities as well as the membrane excitability of NAc neurons, resulting in distorted functional output of NAc neurons. This hypothesis will be tested by pursuing three specific aims: 1) characterize SD-induced synaptic adaptations in NAc neurons; 2) characterize SD- induced membrane adaptations in NAc neurons; and 3) explore the impact of SD on NAc-based emotional and motivational behaviors. The proposed work is closely relevant to NIH's mission in that the expected outcome will provide essential understanding about how sleep and sleep disturbance regulate a key brain region that is involved in a large number of emotional and motivational disorders.